1. Field of the Invention
The present invention relates to methods and veterinary formulations for alleviating and treating chronic pain and improving the performance of ruminant and pre-ruminant animals following painful processing procedures, such as dehorning and castration.
2. Description of Related Art
Cattle processing includes vaccination, castration, dehorning, branding, and identification tagging or implanting prior to, or upon arrival of the cattle at a feedlot or farm. Some of these procedures are viewed as being painful or stressful for the animal. Societal concern about the moral and ethical treatment of animals, including livestock, is becoming more prevalent. Castration is a common procedure in the U.S. beef industry performed on at least 8 million calves per year in the United States alone. However, in addition to acute pain from the procedure castration soon after receipt of long-hauled, highly-stressed bull calves is associated with increased morbidity and mortality and decreased weight gain as compared to steers. Dehorning is another standard cattle management procedure involving the removal of the horns or horn buds of cattle (usually young calves) to prevent injury to other members of the herd, as well as handlers. Negative public perception of pain associated with livestock management procedures such as these has increased, highlighting the need to develop practices to alleviate pain associated with dehorning and castration procedures. Several organizations, including the American Veterinary Medical Association, have stated that pain and physiologic stress of the animals should be minimized (AVMA, 2007). Pain and distress is commonly associated with behavioral, physiological and neuroendocrine changes such as increases in plasma cortisol concentrations. Although it has been reported that non-steroidal anti-inflammatory drug (NSAID) administration attenuates plasma cortisol response, there are currently no drugs specifically approved for pain relief in livestock in the United States (Coetzee et al., 2007; FDA, 2006).
Pain is defined as an aversive sensory or emotional experience representing awareness by the animal of actual or potential tissue damage. Pain is associated with physiological, behavioral and neuroendocrine changes aimed at reducing or avoiding tissue damage, limiting pain reoccurrence and promoting recovery. Pain perception (e.g., nociception) involves the transduction of chemical signals at the site of injury into electrical energy. This is followed by transmission of the electrical signal via nerve fibers up the spinothalamic tracts to the brain where pain perception occurs. The initial response to a noxious stimulus is typically brief, well-localized and somewhat proportional to the intensity of the insult. The second phase of the response is prolonged, diffuse and often associated with hypersensitivity around the point where the initial stimulus was applied. This effect may lead to persistent post-injury changes in the central nervous system resulting in pain hypersensitivity or central sensitization (“wind-up”).
Surgery-induced pain and central sensitization consist of two phases: an immediate incisional phase and a prolonged inflammatory phase that arises primarily due to tissue damage. Several methods have been developed to directly or indirectly assess pain associated with dehorning and castration in calves. Measurements of physiological changes include assessment of heart rate (Heinrich et al., 2009) and heart rate variability (Stewart et al., 2009) and changes in peripheral vascular perfusion determined by thermography (Stewart et al., 2009). Physiological effects of dehorning have also been evaluated by assessing changes in body weight and performance (Faulkner and Weary, 2000). Neuroendocrine effects have been studied using circulating biomarkers such as cortisol (Stafford and Mellor, 2005) and substance P (Coetzee et al., 2008). Behavioral responses to painful events have been assessed using constant video surveillance, chute exit speed determination (Burrows and Dillon, 1997), step counts and stride length (Currah et al, 2009). Remote accelerometer sensors have also been used to objectively monitor cattle behavior, and this system has been validated with high accuracy, compared to video observation, in predicting cattle activity (Robert et al, 2009). Accelerometers have even been used to illustrate behavioral changes in cattle after castration (White et al., 2008), but this technology has not been evaluated in calves after dehorning or in calves given pre-emptive analgesia.
Studies demonstrating the adequacy of preemptive analgesia must meet two basic requirements (Kissin, 2000). The first is to verify the effectiveness of a treatment by demonstrating a direct pharmacological effect. This can be accomplished by comparing differences in acute biomarkers of pain and distress, such as cortisol response and heart rate, between treated and control subjects. It is noteworthy that plasma concentrations of NSAIDs and their actions at the molecular level are not in phase (Lees et al, 2004). This may lead to hysteresis in the relationship between drug concentration and effect and may explain why drug effects do not correspond with peak drug concentration. The second requirement is to demonstrate extension of the anti-nociceptive effect into the postoperative period when pain due to inflammation becomes the dominant process (Kissin, 2000). In practical terms, two approaches have been used to demonstrate the efficacy of preemptive analgesic regimens. The first is to demonstrate a reduction in pain intensity beyond the presence of the drug in the biophase in treated and untreated control subjects. The second approach is to demonstrate that a treatment applied before surgery is more effective than the treatment applied at the end of surgery (Kissin, 2000).
Several compounds including opioids (eg. butorphanol), local anesthetics (eg. lidocaine), α2-adrenergic receptor agonists (eg. xylazine) and NMDA receptor antagonists (eg. ketamine) exert direct analgesic effects by targeting specific receptors in the central and peripheral nervous system. In contrast, NSAIDs produce analgesia and reduce inflammation by inhibiting the enzyme cyclooxygenasc (COX) and subsequent prostaglandin production in the peripheral tissues and central nervous system. However, NSAIDs are generally not recognized as having a preventative effect.
Meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is an NSAID of the oxicam class that is approved in the European Union for adjunctive treatment of acute respiratory disease; diarrhea and acute mastitis when administered at 0.5 mg/kg intravenously (IV) or subcutaneously (SC) (EMEA, 2009) to sick animals. Meloxicam is believed to bind preferentially to cyclooxygenase-2 (COX-2), thereby inhibiting prostaglandin synthesis, although definitive evidence of COX-selectivity in calves is deficient in the published literature (Lees, 2009).
With respect to painful processing events, it was recently reported in a survey of North-central and Northeastern United States dairy producers that only 12.4% of dairy owners use local anesthetic nerve blocks and only 1.8% provide systemic analgesia at the time of dehorning (Fulwider et al., 2008). Similarly, only 18% of Wisconsin dairy producers report using local anesthetics prior to dehorning (Hoe et al., 2006). These data are consistent with the results of the recent National Animal Health Monitoring System (NAHMS) survey that reported that only 17.7% of U.S. operations report using analgesics or anesthetics during the dehorning procedure (NAHMS, 2009). In addition, such drugs must be administered almost exclusively intravenously, further decreasing their likelihood of use. That is, due to the unique nature of ruminant digestion, few drugs are available for oral administration. More specifically, for use in cattle and other ruminants, orally administered drugs must be able to withstand the fermentation and alkaline pH of the rumen, but also survive in the highly acidic environment of the fourth stomach. Many drugs are ionized during ruminant digestion decreasing their bioavailability below effective levels. Few studies have been done on the bioavailability of orally administered analgesics in cattle.
The effects of meloxicam administration without local anesthesia on post-surgical behavior and performance in older calves (>16 weeks of age) have also not been described. In addition, the compartmental pharmacokinetics of meloxicam administered intravenously to calves has not been reported. The oral pharmacokinetics of meloxicam have also not been described. If meloxicam administration alone mitigates pain and distress and produces quantifiable performance benefits when administered prior to a painful cattle management procedure, such as dehorning or castration, this would provide producers and veterinarians with a much-needed practical and cost-effective way to reduce pain and distress after dehorning and/or castration. Meloxicam may also have other benefits for the animal's health following painful processing procedures.
For example, bovine respiratory disease (BRD) is the most common and costly disease of feedlot cattle in the United States (Smith, 1998; NAHMS, 2000a). In 1999, most feedlots (97.4%) within 12 states reported an overall BRD incidence of 14.4% (NAHMS, 2000a). Treatment costs for BRD averaged $15.57 per sick animal. Costs are significantly greater when labor, isolation, increased time on feed, mortality, prophylaxis, and meta-phylaxis treatments are considered (NAHMS, 2000a). Current BRD prevention strategies include mass medication of cattle at higher risk of developing BRD with antimicrobials and the use of vaccination. Neither strategy has been very effective at preventing the incidence of BRD cases especially in high risk groups of cattle, such as bulls castrated upon arrival at feedlots. Furthermore, the mass medication of cattle with antimicrobials is under increasing scrutiny due to the risk of development of antimicrobial resistance. The use of an N SAID to mitigate the negative effects of castration may therefore, provide producers with an effective alternative to antimicrobial use. In addition, if such NSAIDs could be administered orally, this would simplify the administration process, making it more likely that producers will use them when processing their cattle.
Pathological (i.e., chronic) pain states which occur in cattle as a result of tissue damage, nerve damage, and inflammation are also frequently associated with pain hypersensitivity. Pain hypersensitivity manifests as hyperalgesia (exaggerated responses to painful stimuli) and allodynia (pain resulting from normally innocuous stimuli). Hyperalgesia has been reported to persist in dairy cattle and lame sheep for at least 28 days after the initial causal lesion has resolved (Ley et al. 1996; Whay et al., 1998). Consequently, chronic pain associated with lameness is considered one of the most significant welfare concerns in dairy cows. Inflammatory pain associated with lameness responds modestly to treatment with NSAIDs, but neuropathic pain is considered to be refractory to the effects of NSAIDs and many opioid analgesics. Therefore, there is a need to identify drugs and drug targets for alleviating chronic pain of neuropathic origin in animals. Gabapentin (1-(aminomethyl) cyclohexane acetic acid) is a drug originally developed for the treatment of spastic disorders and epilepsy in humans (Cheng and Chiou, 2006). The effectiveness of oral gabapentin alone or co-administered with meloxicam for alleviating pain in ruminants has not been reported.